Ioversol was disclosed as useful as a nonionic x-ray contrast agent in U.S. Pat. No. 4,396,598. An intermediate in its production is 5-[N-(2-acetoxyethyl)acetoxyacetamido]-N,N'-bis (2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide, hereinafter "hexaacetate", having the following structure: ##STR1## This compound and its use in producing ioversol are disclosed in Canadian Patent No. 1,198,739, incorporated herein by reference. Hexaacetate, as disclosed therein, may be produced by alkylating a compound of the formula: ##STR2## with a compound of the formula: EQU CH.sub.3 COOCH.sub.2 CH.sub.2 --X
wherein X is halogen or another leaving group, to produce hexaacetate and then hydrolyzing hexaacetate to produce ioversol.
The alkylation procedure may be carried out in the presence of a base, for example sodium methoxide, sodium ethoxide, sodium hydride, sodium carbonate or potassium carbonate. The reaction may also be carried out in the presence of a diluent or solvent such as methanol, ethanol, dimethylsulfoxide (DMSO), dimethylacetamide (DMAC) or propylene glycol. The alkylating agent may be 2-bromoethyl acetate, for example.
The hydrolyzing procedure may be carried out by use of a hydrolyzing agent which may be, for example, sodium methoxide in methanol, ammonia in methanol, trifluoroacetic acid in aqueous methanol, aqueous sodium carbonate, aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous hydrochloric acid, or aqueous hydrobromic acid; or by use of an ion exchange resin in the presence of water, such as an Amberlite.RTM. resin, for example Amberlite.RTM. IR-120 HCP resin.
This procedure has heretofore required isolation and crystallization of substantially pure hexaacetate prior to the hydrolysis step. This has typically been accomplished by the addition of 1,1,2-trichloroethane (TCE) to the "hexaacetate"/DMSO mixture followed by extraction with water to remove DMSO and certain impurities. Some of the TCE is removed by distillation to concentrate the resulting "hexaacetate"/TCE mixture. Amyl acetate is then added, causing "hexaacetate" to crystallize. The crystals are filtered out and dried. This necessitated the use of expensive drying equipment and resulted in appreciable product losses due to less than complete crystallizations.
An alternative method that would eliminate the need for isolation and crystallization, avoiding the need for amyl acetate, and allow hydrolysis to be performed on hexaacetate at higher yields was desired. It is an object of the present invention to meet these needs.